The present invention relates to novel pyrimidine derivatives and to the use of such derivatives and related compounds to inhibit sorbitol dehydrogenase, lower fructose levels, or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. This invention also relates to pharmaceutical compositions and combinations comprising a sorbitol dehydrogenase inhibitor of formula I and an aldose reductase inhibitor and the use of such compositions or combinations to treat diabetic complications. This invention also relates to pharmaceutical compositions containing such pyrimidine derivatives and related compounds. This invention also relates to pharmaceutical compositions and combinations comprising a combination of a sorbitol dehydrogenase inhibitor of formula I and an NHE-1 inhibitor and to the use of such compositions or combinations to reduce tissue damage resulting from ischemia, and particularly to prevent perioperative myocardial ischemic injury.
S. Ao et al., Metabolism, 40, 77-87 (1991) have shown that significant functional improvement in the nerves of diabetic rats (based on nerve conduction velocity) occurs when nerve fructose levels are pharmacologically lowered, and that such improvement correlates more closely with the lowering of nerve fructose than the lowering of nerve sorbitol. Similar results were reported by N. E. Cameron and M. A. Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A (1991). In both of these cases, lowering of nerve fructose was achieved using relatively high does of aldose reductase inhibitors, which inhibit the formation of sorbitol, a precursor of fructose, from glucose via the enzyme aldose reductase.
U.S. Pat. Nos. 5,138,058 and 5,215,990, which are hereby incorporated by reference, each disclose compounds of the formula ##STR2##
where R.sup.1, R.sup.2, R.sup.3.sub.1, R.sup.4 and R.sup.5 are as disclosed therein. Said compounds are disclosed as having utility as tools in screening for aldose reductase inhibitors due to the sorbitol accumulating activity of said compounds. PA1 wherein R.sup.1 through R.sup.5 are defined as disclosed therein. PA1 R is N,N-dimethylamino or isopropyl. PA1 a. a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound in a first unit dosage form; PA1 b. an aldose reductase inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said aldose reductase inhibitor in a second unit dosage form; and PA1 c. a container. PA1 a. a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound in a first unit dosage form; PA1 b. a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said NHE-1 inhibitor in a second unit dosage form; and PA1 a container. PA1 R is N,N-dimethylamino or isopropyl; and PA1 R.sup.1 is (C.sub.1 -C.sub.4)alkyl, benzyl or phenyl, said benzyl and phenyl being optionally substituted with up to three (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halo or nitro. PA1 R is N,N-dimethylamino or isopropyl; and PA1 R.sup.5 is ##STR9## PA1 a. a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound in a first unit dosage form; PA1 b. a glycogen phosphorylase inhibitor (GPI), a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said GPI in a second unit dosage form; and PA1 c. a container. PA1 1. 3-(4-bromo-2-fluorobenzyl)-3,4-dihydro-4-oxo-1-phthalazineacetic acid (ponalrestat, U.S. Pat. No. 4,251,528); PA1 2. N[[(5-trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl}-N-methylglyc ine (tolrestat, U.S. Pat. No. 4,600,724); PA1 3. 5-[(Z,E)-.beta.-methylcinnamylidene]-4-oxo-2-thioxo-3-thiazolideneacetic acid (epalrestat, U.S. Pat. Nos. 4,464,382, 4,791,126, 4,831,045); PA1 4. 3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolin eacetic acid (zenarestat, U.S. Pat. Nos. 4,734,419, and 4,883,800); PA1 5. 2R,4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Pat. No. 4,883,410); PA1 6. 2R,4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Pat. No. 4,883,410); PA1 7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid (U.S. Pat. No. 4,771,050); PA1 8. 3,4dihydro-3-oxo-4-[(4,5,7-trifluoro-2-benzothiazolyl)methyl]-2H-1,4-benzo thiazine-2-acetic acid (SPR-210, U.S. Pat. No. 5,252,572); PA1 9. N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-methyl-benzeneacetamide (ZD5522, U.S. Pat. Nos. 5,270,342 and 5,430,060); PA1 10. (S)-6-fluorospiro[chroman-4,4'-imidazolidine]-2,5'-dione (sorbinil, U.S. Pat. No. 4,130,714); PA1 11. d-2-methyl-6-fluoro-spiro(chroman-4',4'-imidazolidine)-2',5'-dione (U.S. Pat. No. 4,540,704); PA1 12. 2-fluoro-spiro(9H-fluorene-9,4'imidazolidine)2',5'-dione (U.S. Pat. No. 4,438,272); PA1 13. 2,7-di-fluoro-spiro(9H-fluorene-9,4'imidazolidine)2',5'-dione (U.S. Pat. Nos. 4,436,745, 4,438,272); PA1 14. 2,7-di-fluoro-5-methoxy-spiro(9H-fluorene-9,4'imidazolidine)2',5'-dione (U.S. Pat. Nos. 4,436,745, 4,438,272); PA1 15. 7-fluoro-spiro(5H-indenol[1,2-b]pyridine-5,3'-pyrrolidine)2,5'-dione (U.S. Pat. Nos. 4,436,745, 4,438,272); PA1 16. d-cis-6'-chloro-2',3'-dihydro-2'-methyl-spiro-(imidazolidine-4,4'-4'-H-pyr ano(2,3-b)pyridine)-2,5-dione (U.S. Pat. No. 4,980,357); PA1 17. spiro[imidazolidine-4,5'(6H)quinoline]2,5-dione-3'-chloro-7,'8'-dihydro-7' -methyl-(5'-cis) (U.S. Pat. No. 5,066,659); PA1 18. (2S,4S)-6-fluoro-2',5'-dioxospiro(chroman-4,4'-imidazolidine)-2-carboxamid e (U.S. Pat. No. 5,447,946); and PA1 19. 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H),3'-pyr rolidine]-1,2',3,5'(2H)-tetrone (ARI-509, U.S. Pat. No. 5,037,831). PA1 Z in the compound of formula ARI is O or S; PA1 R.sup.1 in the compound of formula ARI is hydroxy or a group capable of being removed in vivo to produce a compound of formula ARI wherein R.sup.1 is OH; and PA1 X and Y in the compound of formula ARI are the same or different and are selected from hydrogen, trifluoromethyl, fluoro, and chloro. PA1 20. 3,4-dihydro-3-(5-fluorobenzothiazol-2-ylmethyl)-4-oxophthalazin-1-yl-aceti c acid [R.sup.1 =hydroxy; X=F; Y=H]; PA1 21. 3-(5,7-difluorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylac etic acid [R.sup.1 =hydroxy; X=Y=F]; PA1 22. 3-(5-chlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R.sup.1 =hydroxy; X=Cl; Y=H]; PA1 23. 3-(5,7dichlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylace tic acid [R.sup.1 =hydroxy; X=Y=Cl]; PA1 24. 3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzoxazol-2-ylmethyl)phthalazin-1-y lacetic acid [R.sup.1 =hydroxy; X=CF.sub.3 ; Y=H]; PA1 25. 3,4dihydro-3-(5-fluorobenzoxazol-2-ylmethyl)-4-oxophthalazin-1-yl-acetic acid [R.sup.1 =hydroxy; X=F; Y=H]; PA1 26. 3-(5,7-difluorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacet ic acid [R.sup.1 =hydroxy; X=Y=F]; PA1 27. 3-(5-chlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R.sup.1 =hydroxy; X=Cl; Y=H]; PA1 28. 3-(5,7-dichlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylacet ic acid [R.sup.1 =hydroxy; X=Y=Cl]; and PA1 29. zopolrestat; 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]-[R.sup.1 =hydroxy; X=trifluoromethyl; Y=H]. PA1 Z in the compound of formula NHE is carbon connected and is a five-membered, diaza, diunsaturated ring having two contiguous nitrogens, said ring optionally mono-, di-, or tri-substituted with up to three substituents independently selected from R.sup.1, R.sup.2 and R.sup.3 ; or PA1 Z in the compound of formula NHE carbon connected and is a five-membered, triaza, diunsaturated ring, said ring optionally mono- or di-substituted with up to two substituents independently selected from R.sup.4 and R.sup.5 ; PA1 wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 in the compound of formula NHE are each independently hydrogen, hydroxy(C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkylthio, (C.sub.3 -C.sub.4)cycloalkyl, (C.sub.3 -C.sub.7)cycloalkyl(C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylcarbamoyl, M or M(C.sub.1 -C.sub.4)alkyl, any of said previous (C.sub.1 -C.sub.4)alkyl moieties optionally having from one to nine fluorines; said (C.sub.1 -C.sub.4)alkyl or (C.sub.3 -C.sub.4)cycloalkyl optionally mono-or di-substituted independently with hydroxy, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkylthio, (C.sub.1 -C.sub.4)alkylsulfinyl, (C.sub.1 -C.sub.4)alkylsulfonyl, (C.sub.1 -C.sub.4)alkyl, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylcarbamoyl or mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylaminosulfonyl; and said (C.sub.3 -C.sub.4)cycloalkyl optionally having from one to seven fluorines; PA1 wherein M in the compound of formula NHE is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; PA1 said M in the compound of formula NHE is optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon or nitrogen with up to three substituents independently selected from R.sup.6, R.sup.7 and R.sup.8, wherein one of R.sup.6, R.sup.7 and R.sup.8 is optionally a partially saturated, fully saturated, or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen optionally substituted with (C.sub.1 -C.sub.4)alkyl and additionally R.sup.6, R.sup.7 and R.sup.8 are optionally hydroxy, nitro, halo, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.4)alkyl, formyl, (C.sub.1 -C.sub.4)alkanoyl, (C.sub.1 -C.sub.4)alkanoyloxy, (C.sub.1 -C.sub.4)alkanoylamino, (C.sub.1 -C.sub.4)alkoxycarbonylamino, sulfonamido, (C.sub.1 -C.sub.4)alkylsulfonamido, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino, carbamoyl, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylcarbamoyl, cyano, thiol, (C.sub.1 -C.sub.4)alkylthio, (C.sub.1 -C.sub.4)alkylsulfinyl, (C.sub.1 -C.sub.4)alkylsulfonyl, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylaminosulfonyl, (C.sub.2 -C.sub.4)alkenyl, (C.sub.2 -C.sub.4)alkynyl or (C.sub.5 -C.sub.7)cycloalkenyl, PA1 wherein said (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.7)alkanoyl, (C.sub.1 -C.sub.4)alkylthio, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino or (C.sub.3 -C.sub.7)cycloalkyl R.sup.6, R.sup.7 and R.sup.8 substituents are optionally mono- substituted independently with hydroxy, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.3 -C.sub.7)cycloalkyl, (C.sub.1 -C.sub.4)alkanoyl, (C.sub.1 -C.sub.4)alkanoylamino, (C.sub.1 -C.sub.4)alkanoyloxy, (C.sub.1 -C.sub.4)alkoxycarbonylamino, sulfonamido, (C.sub.1 -C.sub.4)alkylsulfonamido, amino, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylamino, carbamoyl, mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylcarbamoyl, cyano, thiol, nitro, (C.sub.1 -C.sub.4)alkylthio, (C.sub.1 -C.sub.4)alkylsulfinyl, (C.sub.1 -C.sub.4)alkylsulfonyl or mono-N- or di-N,N-(C.sub.1 -C.sub.4)alkylaminosulfonyl or optionally substituted with one to nine fluorines.
Commonly assigned U.S. Pat. Nos. 5,728,704 and 5,866,578 which are hereby incorporated by reference, discloses a method for treating or preventing diabetic complications that can be treated or prevented by inhibiting the enzyme sorbitol dehydrogenase. That patent also discloses compounds of the formula A, ##STR3##
Further, U.S. Patent Nos., assigned to Hoechst, disclose as having utility in detecting levels of sorbitol dehydrogenase.
We have found that pyrimidine derivatives of the formulas I, II, III and IV, as defined below, and their pharmaceutically acceptable salts, lower fructose levels in the tissues of mammals affected by diabetes (e.g., nerve, kidney and retina tissue) and are useful in the treatment and prevention of the diabetic complications referred to above. These compounds, or their metabolites in vivo, are inhibitors of the enzyme sorbitol dehydrogenase, which catalyzes the oxidation of sorbitol to fructose.